Recovery After Olfactory Cell Transplants with Peripheral Nerve Bridges

Many of you will have seen news stories reporting functional regeneration of connections that enable movement in a man that received transplants of olfactory cells. This approach is a clinical realization of decades of research by a scientist who received our Reeve-Irvine Research Medal in 2005 (Geoff Raisman). The findings are provocative, and the overall study reflects a huge effort by a skilled team of researchers and medical doctors. Unfortunately, though, the situation is not as simple as implied in most of the news stories. So, what is this all about, and what does it mean for those of you living with paralysis?

First the science: the overall approach builds upon years of research on regeneration of nerve connections from the nose to the brain. The ability to smell is mediat ted by nerve cells in the nose called olfactory receptors, which are embedded in a structure called the nasal mucosa, which is made up of receptor cells and mucosal cells. The olfactory receptors respond to chemicals in the air, and communicate via connections (axons) that project into the brain. The olfactory receptors in the nose 'turn over' throughout life (that is, the cells die and others are born), which is different than almost any other part of the nervous system. When new cells are born, they have to grow their axons from the nasal mucosa in the nose into the olfactory bulbs, which are inside the skull. The olfactory bulb is connected to the brain by the olfactory nerve. To grow from the olfactory mucosa to the brain, the axons grow through the bony structure between the nose and the brain called the cribriform plate, and there is lots of evidence that growth is enabled by a special population of glial cells there called olfactory ensheathing cells (OECs). Dr. Raisman and other scientists have provided strong experimental evidence that OECs have special properties in terms of supporting axon growth, and many scientists have tried different ways of transplanting either OECs or the entire nasal mucosa into the injured spinal cord to promote regeneration.

Based on the studies in animals, quite a few people throughout the world have received a highly experimental therapy involving transplants of olfactory mucosa into the spinal cord. This experimental therapy is not available in the United States, but has been offered in Portugal and elsewhere, and some Americans have traveled to other countries to receive the transplants. These weren’t clinical trials, however; they were experimental therapies without controls or followup testing, so there’s no scientific data on outcomes. Also, there are concerns about the approach of transplanting olfactory mucosa because of the recent finding of a tumor that developed in the spinal cord in a patient that received such a transplant (see our Spring 2014 newsletter).

It’s important to emphasize that this new study involves cells that were isolated from the olfactory mucosa, not the olfactory mucosa itself, so the risk of tumor formation is hopefully less. Another good thing about this new study is that it was actually a clinical trial with an experimental and control group with extensive pre- and post-operative testing, so there is a lot of data. The patients were a total of 6 men between the ages of 22 and 26; 3 patients received the treatment, 3 did not, and all were tested extensively. The study reported outcomes 1 year after cell transplantation. The treatment in this new study, which was carried out in Warsaw Poland, was to transplant OECs that were harvested from the patient (autologous transplants) along with small pieces of peripheral nerves that were inserted to provide a bridge across the injury site. The first step was a complicated surgery to remove the olfactory mucosa.

The olfactory mucosa was then dissociated (meaning broken up so that individual cells are in a mixture—imagine rice mixed with water) and the cells were transferred to a tissue culture dish for several days. The cells were characterized extensively while growing in culture, and at the end of the cell culture period contained OECs as well as other cell types. Then, each patient received another surgical procedure to open the spine and visualize the spinal cord so that the transplant could be done. Then, there was a lot of rehabilitation and testing.

Of the 3 people who received transplants, 2 exhibited improved function on the ASIA scale, the third did not improve on the ASIA scale, but did experience some improvement in sensation just below the injury. The main recovery in all patients was between 6 and 12 months post-transplant. For the man who was featured in the news reports who exhibited the greatest recovery, the first signs of recovery were 6 months following the treatment, and involved tingling sensations below the injury. By 8 months, the patient recovered some ability to feel touch below the injury. By 1 year, the patient had '…a slight voluntary flexion of the right hip' which qualified for conversion of the ASIA grade from A to C.

"...patients who underwent the operation of OEC transplantation combined with intense pre- and post-operative neurorehabilitation showed modest neurological signs of recovery."

It’s important to emphasize how the authors summarized the results: '… patients who underwent the operation of OEC transplantation combined with intense pre- and postoperative neurorehabilitation showed modest neurological signs of recovery.' This highlights the fact that was a carefully done and carefully interpreted study with a lot of details, although even with that, some of the claims are provocative. The title of the article claims “functional regeneration” (meaning growth of axons across the injury site). This claim was based largely on neurophysiological studies involving stimulation and recording of muscle responses (motor evoked potentials). This would be extraordinary if true. The authors were actually a lot more conservative in the paper itself, noting that even when injuries are functionally complete, there are usually some spared connections that could recover the ability to transmit. In fact, the authors conclude that the neurological recovery in transplanted patients may have been '…a combination of remyelination of spared demyelinated axons, stimulation of regeneration of lesioned axons towards the target host neurons, and reactivation or sprouting of surviving axons.'

It’s also important to note that the man who was featured in the news reports became paralyzed as a result of a stab injury, which caused extensive but incomplete laceration of the spinal cord leading to paralysis of the legs. This is a different situation than occurs with most spinal cord injuries that result from blunt force trauma like car accidents, diving injuries and falls, which cause contusion injuries. It is possible that the greater recovery in this patient is due to the type of injury.

So, the important thing is that this study was carefully done and produced a lot of scientific data that will form the basis for future studies. The surgical and cell culture procedures used here are complicated, and even in the best case, the neurological recovery was modest. The cost of the therapy would likely be several hundred thousand dollars per patient because of two surgical procedures, the lab work to grow the cells, and intense rehabilitation that extended for months. Only time will tell whether this could ever be adopted as a practical and effective therapy.

Reference: Tabakow, P., G. Raisman, W. Fortuna, M. Czyz, J. Huber, D. Li, P. Szewczyk, S. Okurowski, R. Miedzybrodzki, B. Czapiga, B. Salomon, A. Halon, Y. Li, J. Lipiec, A. Kulczyk and W. Jarmundowicz (2014). "Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging." Cell Transplant